Project Summary/Abstract The cerebellar vermis is increasingly implicated neuropsychiatric illnesses such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). It has structural and functional connectivity to regions beyond the motor brain, including the prefrontal cortex, hippocampus, and amygdala, as well as functional connectivity with multiple neural networks including the default mode, fronto-parietal, and salience networks. Evidence suggests the vermis may affect cognition and emotion through modulation of neural activity and temporal dynamics within neural networks with which it interconnects. As shared involvement of specific cortical networks including those with connectivity to the vermis and common genetic and environmental risk factors are increasingly evident among SCZ, BD, and MDD, vermis abnormalities and how they may alter cortical network modulation could have key roles in the neural mechanisms that lead to the similarities and differences in impairments and clinical features across SCZ, BD, and MDD. Intriguingly, vermis stimulation has led to cognitive and emotional changes in SCZ, although with mixed results due to limited understanding of how the vermis is involved in SCZ and neuropsychiatric disorders in general. Nevertheless, prior findings strongly support the significant involvement of the vermis in neuropsychiatric illnesses and its potential use in novel treatments for these illnesses. The vermis has largely been understudied in SCZ, BD, and MDD, and current understanding of its functional topography is still in nascent stages. A more systematic examination of the vermis across SCZ, BD, and MDD is clearly needed. This would provide greater understanding of the important interplay between the vermis and cortical networks in SCZ, BD, and MDD and could advance the development of novel treatments using vermis stimulation in these disorders. The proposed project will utilize structural and functional magnetic resonance imaging techniques and complementary methods to further delineate the nature of vermis abnormalities across SCZ, BD, and MDD and their relationship to cognitive function. Through a strong international collaboration, the proposed study will expand upon an ongoing, independently funded data collection in a large unique sample in China that includes a significant proportion of first episode and medication nave individuals. At present, this sample consists of 297 healthy controls (HC) and 216, 180, and 204 individuals with SCZ, BD, and MDD, respectively, from ages 13 to 65 years old, including total 240 first episode (105, 41, and 94) and 147 medication nave (49, 30, and 68) individuals (SCZ, BD, and MDD, respectively). Aim 1 of the proposed study will determine differences in vermis volumes between SCZ, BD, MDD, and HC groups. Aim 2 will determine differences in resting state functional connectivity of vermis subregions with four neural networks, default mode, fronto-parietal, cingulo-opercular, and salience networks in SCZ, BD, MDD, and HC. Aim 3 will determine the relationship of cognitive measures to vermis volumes and resting state functional connectivity across SCZ, BD, MDD, and HC. Given the importance of early development in vermis structure and function and across SCZ, BD, and MDD, all aims will incorporate neurodevelopmental considerations of prenatal patterning during vermis development and sex to bridge early developmental considerations with vermis alterations at later developmental stages. Inclusion of neurodevelopmental considerations could improve understanding of the developmental processes in SCZ, BD, and MDD. Further, the proposed study would address knowledge gaps in how the vermis is involved across SCZ, BD, and MDD and how it could be utilized in novel treatment interventions for these debilitating illnesses. The proposed transdiagnostic approach would provide greater insight into the similarities and differences in brain structure and function across SCZ, BD, and MDD. In addition, the proposed complementary methods for vermis analyses could have implications for the use of more automated methods to examine the vermis in research and clinical settings. Altogether, the proposed study could have significant contributions for understanding the neuropathophysiology of SCZ, BD, and MDD and advancing diagnostic and treatment strategies for these disorders.